In patients with heart failure with a preserved ejection fraction (HFpEF), the prescribed treatments for managing comorbid hypertension do not seem to improve mortality as they do in other heart failure patients. Now MUSC researchers want to know why. In patients with HFpEF, whoaccount for about half of all heart failure cases, the ventricles gradually thicken and stiffen, preventing normal relaxation from beat to beat. The underlying myocardial changes responsible for HFpEF development have proven elusive, providing a major challenge for cardiologists who seek to treat HFpEF patients. Using a translational approach, MUSC researchers and their colleagues are the first to address this challenge directly.

MUSC Health cardiologistsMichael R. Zile, M.D.,andJohn S. Ikonomidis, M.D., Ph.D., along with their MUSC colleaguesCatalin Baicu, Ph.D.andAmy Bradshaw, Ph.D., suspect that changes in certain fibrous proteins contribute to left ventricle relaxation deficits in HFpEF patients. Emerging data from a study led by Zile and published in the April 7, 2015 issue of Circulation1examined changes in collagen and titin, two major fibrous proteins that constitute the physical scaffold necessary for normal relaxation in the heart. Using small myocardial muscle strips extracted from the hearts of 70 cardiac bypass surgery patients, Zile’s group discovered that a measure of ventricular muscle tension during relaxation, called passive stiffness, was pathologically increased in those patients with HFpEF. Just as suspected, this increase was dependent on changes in both collagen and titin. Importantly, these changes were only detected in patients with both hypertension and HFpEF.Moreover, biomarkers in patient plasma reflecting changes in collagen correlated with the presence and severity of HFpEF.

This work, undertaken at MUSC in collaboration with other centers, is the first to use tissue from HFpEF patients to pinpoint specific changes in titin and collagen as important underlying drivers of HFpEF development.How can this new information be used to help patients?Zile states that MUSC scientists are already collaborating with major pharmaceutical partners to develop new biomarker tools for HFpEF detection.“Proteins and peptidesthat indicate changes in collagen in the heart can be easily measured in small amounts of blood,” says Zile. “These biomarkers can be used to help make early diagnosis and predict prognostic outcomes in HFpEF patients. The arrival for these novel applications is just over the horizon.”

The summer of 2015 saw approval of the first new drug for heart failure in almost two decades. The angiotensin receptor–neprilysin inhibitor Entresto (formerly LCZ696, Novartis Pharmaceuticals) was approved for heart failure with reduced ejection fraction (HFrEF) on the basis of the results of the PARADIGM-HF trial published in the September 11, 2014 issue of the New England Journal of Medicine.1 MUSC Health cardiologist Michael R. Zile, M.D., who served on the national steering committee of the PARADIGM-HF trial, predicts that the new therapy “will replace ACEs and ARBs as the cornerstone of standard therapy for patients with HFrEF.”

However, patients with HFrEF account for only about half of the 3 million heart failure cases in the U.S. each year. No agent has been shown to improve morbidity and mortality in patients with heart failure with preserved ejection fraction (HFpEF), who make up the other half of heart failure cases. In patients with HFrEF, the left ventricle does not fully contract, while in those with HFpEF, the ventricle does not fully relax. The two largest clinical trials to date showed that traditional heart failure therapy with angiotensin receptor blockade (Irbesartan or Candesartan) did not improve heart function in patients with HFpEF. According to Zile, “The biggest unmet need in cardiology today is a treatment for HFpEF.”

That could be changing. Zile is on the national steering committee of the PARAGON-HF trial, which will assess the efficacy of Entresto in patients with HFpEF, and MUSC Health is one of the sites enrolling patients into the trial. Results are expected in 2017. “PARAGON-HF will be largest clinical trial in patients with HFpEF,” says Zile. “We hope that Entresto will form the foundation for novel and effective treatment that reduces symptoms and increases survival in HFpEF.”